Mice lacking a particular enzyme exhibit abnormal immune responses, resulting from a less than perfect fit of protein bits displayed to immune cells, according to a paper in January's Nature Immunology.
Nilabh Shastri and colleagues show that mice lacking the enzyme ERAAP fail to cleave antigenic proteins properly. Their results suggest immune cell recognition of tumors or virally infected cells might depend on ERAAP activity.
The immune system is constantly on the lookout for sick cells. Immune cells distinguish healthy cells from infected or abnormal cells by the array of peptides (small bits of protein) displayed on their surface by specialized molecules known as major histocompatibility complex (MHC) proteins. First recognized as important for tissue matching in transplantation studies, MHC proteins present snapshots of the protein repertoire found inside the cell. This 'peptide presentation' involves coordinated cleavage of cellular proteins into peptides and loading of this peptide cargo into a groove found on the MHC molecule, whereupon peptide-MHC complexes travel to the cell surface where they are 'sampled' by the circulating immune cells.
ERAAP, which stands for "endoplasmic reticulum aminopeptidase associated with antigen processing", trims peptides in the ER and thereby allows peptides to 'fit' better in the MHC groove. Shastri and colleagues show loss of ERAAP decreases the stability of peptide-MHC interactions, which results in less MHC expressed on cell surfaces and those MHC molecules that do make it to the surface readily lose their peptide cargo or display altered peptide repertoires. ERAAP-deficient mice mount weaker immune responses to foreign antigens. ERAAP can thus be considered as a quality control enzyme required for proper immune cell recognition.
Nilabh Shastri (University of California Berkeley, CA, USA)
Abstract available online.
(C) Nature Immunology press release.
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